Sophisticated lung imaging can show whether or not a treatment drug is able to clear tuberculosis (TB) lung infection in human and macaque studies, according to researchers at the University of Pittsburgh School of Medicine and their international collaborators.
The findings, published online today in Science Translational Medicine, indicate the animal model can correctly predict which experimental agents have the best chance for success in human trials.
The image on the left shows "hot spots" of infection in a patient's lungs before treatment. The image on the right shows the disease improvement after six months of taking the drug linezolid.
In 2012, an estimated 8.6 million people in the world contracted TB, for which the first-line treatment demands taking four different drugs for six to eight months to get a durable cure, explained senior investigator JoAnne L. Flynn, Ph.D., professor of microbiology and molecular genetics, Pitt School of Medicine. Patients who aren't cured of the infection - about 500,000 annually - can develop multi-drug resistant TB, and have to take as many as six drugs for two years.
"Some of those people don't get cured, either, and develop what we call extensively drug-resistant, or XDR, TB, which has a very poor prognosis," she said.
"Our challenge is to find more effective treatments that work in a shorter time period, but the standard preclinical models for testing new drugs have occasionally led to contradictory results when they are evaluated in human trials."
In previous research, Dr. Flynn's colleagues at the National Institutes of Health found that the drug linezolid effectively treated XDR-TB patients who had not improved with conventional treatment, even though mouse studies suggested it would have no impact on the disease.
To further examine the effects of linezolid and another drug of the same class, Dr. Flynn and her NIH collaborators, led by Clifton E. Barry III, PH.D., performed PET/CT scans in TB-infected humans and macaques, which also get lesions known as granulomas in the lungs. In a PET scan, a tiny amount of a radioactive probe is injected into the blood that gets picked up by metabolically active cells, leaving a "hot spot" on the image.
The researchers found that humans and macaques had very similar disease profiles, and that both groups had hot spots of TB in the lungs that in most cases improved after drug treatment. CT scans, which show anatomical detail of the lungs, also indicated post-treatment improvement. One patient had a hot spot that got worse, and further testing revealed his TB strain was resistant to linezolid.
The findings show that a macaque model and PET scanning can better predict which drugs are likely to be effective in clinical trials, and that could help get new treatments to patients faster, Dr. Flynn said. The scans also could be useful as a way of confirming drug resistance, but aren't likely to be implemented routinely.
"We plan to use this PET scanning strategy to determine why some lesions don't respond to certain drugs, and to test candidate anti-TB agents," she said. "This might give us a way of tailoring treatment to individuals."
The research team includes lead author M. Teresa Coleman and others from the Pitt School of Medicine and Children's Hospital of Pittsburgh of UPMC; co-senior author Dr. Barry and others from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health; as well as scientists from the International Tuberculosis Research Center in Changwon, Republic of Korea; Rutgers New Jersey Medical School; Frederick National Laboratory for Cancer Research; Yonsei University College of Medicine, Seoul, Republic of Korea; and the University of Cape Town, Rondebosch, South Africa.
Funding for this study was provided by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; the Ministry of Health and Welfare, Republic of Korea; and the Bill and Melinda Gates Foundation.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu
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